ABSTRACT Skin inflammatory diseases, such as atopic dermatitis and psoriasis, are thought to be driven by the interplay between the immune system and structural cells present in the epidermis or dermis. Features of these diseases include tissue remodeling which can be excessive deposition of collagen and other extracellular matrix proteins in the dermal and/or adipose layers, vascular damage, immune cell infiltration, and/or epidermal hyperplasia. Primary cells that can contribute to skin inflammation include T cells, fibroblasts, keratinocytes, and macrophages, with additional contributions of neutrophils, mast cells, and eosinophils depending on the specific disease. Collagen and other extracellular matrix protein deposition is thought mediated primarily by deregulation of fibroblasts, and driven by secreted products from inflammatory cells like Th2 or Th17 cells. These cytokines, which include IL-13 or IL-17, also contribute to end-stage pathology in atopic dermatitis and psoriasis, through direct actions in promoting epidermal hyperplasia and through production of additional soluble mediators such as chemokines from keratinocytes. The discovery of new and novel protein targets that perform similar, alternate, or synergistic actions is of strong interest, especially if these proteins are active in promoting skin inflammation in both atopic dermatitis and psoriasis. We have recently shown that a TNF family protein, called TWEAK (TNFSF12), that interacts with the TNFR superfamily molecule Fn14, when injected into the skin of mice, can promote features of both atopic dermatitis and psoriasis, including dermal and epidermal thickening, and upregulation of inflammatory cytokines that are seen in patients with both diseases. Correspondingly, mice that are deficient in TWEAK are strongly protected from developing skin inflammation in models of atopic dermatitis and psoriasis. From analysis of human cells, we have found that Fn14 is expressed in keratinocytes and dermal fibroblasts, and preliminary data suggests that TWEAK can have strong effects on these cells linked to skin inflammation. This proposal will focus on in vivo mouse models of atopic dermatitis and psoriasis, complemented with in vitro studies of mouse and human structural cells implicated in driving skin inflammation, and determine how TWEAK contributes to skin inflammatory disease, delineate what are its cellular and molecular targets, understand how TWEAK signals integrate with those from IL-13 and IL-17, and test whether TWEAK and Fn14 represent new targets for therapeutically dampening or reversing skin inflammatory disease.